tbuckley/cabot-search huggingface dataset:
Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): An international randomised trial.
Authors: Mohammed Abu Hilal, Maarten Korrel, Leia Jones, Jony van Hilst, Bergthor Björnsson, Ugo Boggi, Svein Olav Bratlie, Giovanni Butturini, Riccardo Casadei, Bjørn E. Edwin, Alessandro Esposito, Massimo Falconi, Bas Groot Koerkamp, Tobias Keck, Ruben de Kleine, Arto Kokkola, Daan Lips, Misha Luyer, Alessandro Zerbi, Marc G. Besselink
Journal: Journal of Clinical Oncology (2023)

4163 Background: In the absence of randomised trials, the oncological safety of minimally invasive distal pancreatectomy (MIDP) in patients with pancreatic cancer continues to be a matter of debate. Methods: An international randomised non-inferiority trial including patients with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, &lt;1mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients who did not undergo a resection. The pre-defined non-inferiority margin was set at -7%. Results: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). The modified intention-to-treat population included 117 patients in the MIDP group and 114 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 4%, 90% CI -6 to 14%; p=0.039). Median lymph node yield was comparable (22.0 [16.0-30.0] vs 23.0 [14.0-32.0] nodes, p=0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p=0.45). Other postoperative outcomes were comparable. Conclusions: In this trial, the rate of radical resection following MIDP was non-inferior compared to ODP. This confirms the oncological validity of the minimally invasive approach in patients with resectable pancreatic cancer. Clinical trial information: ISRCTN44897265 .
A comparison between a clinical decision support system and clinicians with guidelines in breast cancer.
Authors: Jianbin Li, Yang Yuan, Li Bian, Hua Yang, Li Ma, Ling Xin, Feng Li, Shaohua Zhang, Tao Wang, Yinhua Liu, Zefei Jiang
Journal: Journal of Clinical Oncology (2023)

e13551 Background: We are building a clinical decision support system (CSCO AI) for breast cancer patients to improve the efficiency of clinical decision-making. We aimed to assess cancer treatment regimens, in neoadjuvant therapy, adjuvant chemotherapy, adjuvant endocrine therapy, first line therapy and second line therapy, given by CSCO AI and clinicians. Methods: 400 breast cancer patients were screened from the CSCO database. Clinicians with similar levels were randomly assigned one of the volumes (200 cases). After that, clinicians with guidelines were asked to answer the same cases again. CSCO AI was asked to assess all cases. Three reviewers were independently asked to evaluate the regimens from clinicians and CSCO AI. Regimens were masked before evaluation. The primary outcome was the proportion of high-level conformity (HLC), which were defined as the proportions of regimens in accordance with CSCO guidelines. Results: The overall concordance between clinicians and CSCO AI was 67.4% (2350/3500). After referring to the guideline, a total of 22.6% (792/3500) regimens were modified by clinicians, 12.9% (451/3500) had a higher grades and 9.7% (341/3500) had a lower grades. In early stage, the concordance was elevated with statistical significance from 71.3% (1497/2100) to 76.1% (1598/2100, p＜0.001). In the metastatic stage, the concordance was improved form 61.7% (864/1400) to 66.0% (924/1400, p=0.018). HLC in CSCO AI was 95.8% (95%CI:94.0%-97.6%), significantly higher than that in clinicians (90.8%, 95%CI:89.8%-91.8%) and in clinicians with guidelines (92.1%, 95%CI:91.0%-93.4%). In early stage, high-level conformity in CSCO AI was 95.7%, with no statistical significance when compared with clinicians (92.7%, p=0.078) and clinicians with guidelines (92.3%, p=0.050). In metastatic stage, high-level conformity in clinicians was only 88.0%, lower than that in CSCO AI (96.0%, p=0.001). However, after referring guidelines, high-level conformity in clinicians was elevated to 91.9%, with no significant difference when compared with that in CSCO AI (p=0.058). Considering professions, the high level conformity of surgeons was 85.9%, lower than that of CSCO AI (OR=0.25,95%CI: 0.16-0.41). The most significant difference in HLC was in first-line therapy (OR=0.06, 95%CI:0.01-0.41). When clinicians were divided according to their levels, there was no statistical significance between CSCO AI and higher-level clinicians. Conclusions: Clinical decision support for breast cancer was superior for most process outcomes except for second-line therapy. The improvements in process outcomes suggest that CSCO AI can be widely used in clinical practice.
A multicenter retrospective study of timing of chemoradiation in high-risk, grade 2, IDH-mutated astrocytoma.
Authors: Tresa McGranahan, Tyler Ashford Lanman, Isabella Densmore
Journal: Journal of Clinical Oncology (2023)

e14035 Background: Patients with Grade 2 IDH mutated astrocytoma that have residual disease after surgery are characterized as high risk. There is limited data to guide timing of treatment for these patients so treatment guidelines recommend either adjuvant chemoradiation or observation delaying adjuvant treatment until disease progression (OBS). This study sought to evaluate the clinical characteristics and survival of patients with Grade 2 IDH mutated astrocytoma treat with adjuvant temozolomide (TMZ) based chemoradiation (tRT) compared to patients treated with observation following surgery. Methods: We conducted a multicenter retrospective study of patients with histologic grade 2 IDH mutated astrocytoma treated at the University of Washington and Stanford Medical Center. To evaluate the impact of treatment, tRT was defined as treatment decision at time of diagnosis to treat with radiation in combination with concurrent and or adjuvant TMZ. Extent of resection and progression were determined based on the treating neuro-oncologists notes. Survival probability, overall survival (OS) and time to first progression (PFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in GraphPad Prism. Results: A total of 115 patients were identified with a median follow up of 6.54 years (y). For the whole cohort, median overall survival (mOS) was 15.5y and median progression free survival (mPFS) was 4.9y. For the whole cohort, 29 patients were treated with tRT and 58 with OBS. tRT improved PFS compared to OBS (p=0.044) with mPFS 6.17y v. 3.58y. There was no difference in OS (p=0.11) as the mOS for tRT was 12.8y v. 15.5y. For the patients with residual disease after surgery, 24 patients were treated with tRT and 26 with OBS with a median follow up of 5.3y. Treatment with tRT trended towards improved PFS (6.2y) compared to OBS (3.5y) (p=0.061). There were no significant difference in demographics of these high risk patients. For OBS patients, 6 had tRT at progression in the range of 0.9y to 25.4y and median time of 2.4y. Conclusions: This multicenter retrospective study found that for Grade 2 IDH mutated astrocytoma, tRT treatment following surgery with residual disease improved PFS but did not impact mOS. However in high risk patients, tRT did not impact either PFS or OS. This study further confirmed the protracted natural history of this disease and supports observation as a treatment option for patients with Grade 2 IDH mutated astrocytoma, even for high risk patients who underwent biopsy or subtotal resection. [Table: see text]
Molecular and immune analysis of adrenocortical carcinoma (ACC): Implications for immune checkpoint inhibition (ICI).
Authors: Bassel Nazha, Nishant Gandhi, Abdul Rafeh Naqash, Matthew James Hadfield, Tony Zhuang, Jacqueline T. Brown, Bradley Curtis Carthon, Pedro C. Barata, Neeraj Agarwal, Heloisa P. Soares, Omer Kucuk, Jamie Goldman, Emil Lou, Farah Rukshana Abdulla, Matthew James Oberley, Alex Patrick Farrell, Viraj A. Master, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2023)

e16617 Background: ACC is a rare and aggressive malignancy. Response rates to ICI are low with scarce yet promising durable responses. Molecular ACC subtypes have been reported based on The Cancer Genome Atlas (TCGA). Here we report the mutational and immune landscapes of ACC obtained from a real-world patient dataset. Methods: DNA (592-gene or whole exome; N=215) and RNA sequencing (whole transcriptome; N=121) were performed for ACC specimens submitted to Caris Life Sciences (Phoenix, AZ). PD-L1+ expression was tested by IHC (SP142; ≥1%). Hierarchical agglomerative clustering (HAC) analysis was performed on a pre-defined set of immune genes. Specimens grouped into immune-high/intermediate (IH) and immune-low (IL) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate immune cell infiltrates. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q&lt;0.05). Results: Overall, the most frequent mutations were in TP53 (37%), CTNNB1 (18.7%), ATRX (12.1%), NF1 (9.6%), and RB1 (8.75%), consistent with previous reports. Further, 6.4% of tumors were PD-L1+, 6.1% TMB-high (≥ 10 mut/MB), and 5.9% dMMR/MSI-H. 38.2% of tumors were biopsied from metastatic sites (M). Compared to M, primary (P) specimens had a higher prevalence of TP53 (43.4 vs 26.9%, p&lt;0.05) and TERT promoter mutations (11.1 vs 0%, p=0.08), and a lower prevalence of SMARCB1 (0 vs 3.7%, p=0.054) and BRCA2 (0 vs 3.8%, p=0.056) mutations. Interestingly, M lesions were enriched for HAVCR2 expression (1.3-fold, p&lt;0.05), as well as infiltration of monocytes (1.8-fold, q&lt;0.05) and endothelial cells (1.4-fold, q&lt;0.05). HAC based segregation of tumors based on immune activity was corroborated by a general enrichment of immune cell infiltrates in the IH tumors. IH tumors were enriched for common immunotherapy-related biomarkers (TMB-high, dMMR/MSI-H and PD-L1 positivity), along with a higher prevalence of TP53 and ATRX mutations, while CTNNB1 mutation and CDK4 copy number amplification were less common in IH tumors. Conclusions: Querying a large real-world ACC patient dataset, we find somatic alterations and a low prevalence of ICI-related biomarkers (&lt;10%), consistent with previous reports. Monocyte and endothelial cell infiltration in metastatic tumors suggests an immunosuppressive phenotype compared to primary tumors. Finally, identification of molecular alterations in tumors with distinct immune phenotypes may facilitate development of new therapeutic strategies in ACC. [Table: see text]
Development of a novel blood-based RNA gene expression platform for early-stage lung cancer diagnosis.
Authors: Martin J Keiser, Elizabeth Cormier-May, Matthew Alderdice, Joy N Kavanagh, Brendon Matthew Stiles
Journal: Journal of Clinical Oncology (2023)

8557 Background: Blood-based methods using circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) are under development for early and less invasive detection of lung cancer, although detection of the earliest stage cancers (stages 0-II) using these modalities is suboptimal. We hypothesized that a machine learning approach using RNA gene expression may offer important information on the biology of the patient, allowing for gene expression profiles to be used as a surrogate measurement of cancer disease phenotype and as a promising direction for early detection of lung cancer. In a previous study, 23 miRNA biomarkers were successfully discovered and validated for the non-invasive diagnostic classification of lung adenocarcinoma, achieving 97.7% sensitivity, 98.7% specificity in blood obtained from 383 clinical subjects. The aim of this study was to train a machine learning algorithm, from the 23 miRNA features, to test the signature for early lung cancer detection. Methods: A large and diverse clinical cohort was obtained from the NIH Gene Expression Omnibus database, GEO Accession Number GSE137140 ( n=3,744), comprised of miRNA extracted from serum samples consisting of subjects with pre-operative lung cancer ( n=1,566) and non-cancer controls ( n=2,178). Our analytic plan leveraged machine learning methods derived from XGBoost classification, a popular supervised-learning algorithm that uses sequentially built shallow decision trees to provide accurate results and avoidance of overfitting. The algorithm was trained using XGBoost 1.4.1.1 R library programmed with R v3.6.3. Results: The lung cancer cohort was heavily weighted towards early-stage lung cancer (87.7% stage I/II), including representation across prevalent histologic types (adenocarcinoma 77.8%, non-adenocarcinoma 22.2%) and those who self-reported as never smokers (37.9%). The 23-miRNA signature achieved 98% sensitivity, 89% specificity in the held-out test set (Table). When incorporating age and gender, the 23-miRNA signature achieved 95.5% sensitivity, 90.3% specificity. Conclusions: A machine learning approach using RNA gene expression in patient serum achieved high sensitivity and specificity in a large, predominantly early-stage, lung cancer cohort. A multi-analyte, multimodal approach that leverages machine learning algorithms with RNA gene expression profiles and available demographics and clinical risk-factors, represents the possibility to accurately detect lung cancer in the earliest stages. This approach has successfully been translated from microarray to PCR instrumentation, with further validation of this machine learning method and approach currently underway. [Table: see text]
Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
Authors: Rebecca A Sager, Philippe E. Spiess, Roger Li, Petros Grivas, Ashish M. Kamat, Andrea Necchi, Dean C. Pavlick, Richard S.P. Huang, Douglas I. Lin, Jeffrey S. Ross, Natalie Danziger, Joseph M Jacob, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2023)

5044 Background: TMB has emerged as a novel biomarker of immune checkpoint inhibitor (ICPI) response in a wide variety of malignancies, but not yet in PSCC. Methods: 397 clinically advanced PSCC underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). TMB was determined on up to 1.1 Mb of sequenced DNA and categorized into three groups: &lt;10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and &gt;20 muts/Mb (very high). MSI was determined on 114 loci. Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and PD-L1 expression by IHC (TPS and Dako 22C3). Statistical comparisons utilized the Bonferonni correction method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases. The mean age of PSCC with very high TMB at 70.1 yrs was older than TMB low at 63.4 yrs (p=.08). The GA per tumor frequencies ranged from 5.4 to 5.5 in the 3 groups. There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% in the TMB 10-19 and 11.8% in the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than TMB low (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. In total, 6.5% of all GA were predicted to be of germline nature. The highest proportions of germline GA were seen for HRR genes ATM and CHEK2 (both 40%) and BRCA2 (37.5%) and PMS2 (40%) linked to Lynch syndrome. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for TMB low, 50.0% for TMB high and 58.8% for TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels reveals significant differences in biomarkers for the near 15% of cases that have TMB ≥10 muts/Mb. TMB and MSI status can also serve as biomarkers of response to SOC anti-PD1 based on the current FDA indications. These data may be useful to provide rationale for inclusion of PSCC in basket or umbrella trials testing novel monotherapies or combination therapies. [Table: see text]
Preclinical efficacy of NXP900, a YES1/SRC kinase inhibitor in esophageal squamous cancer models.
Authors: Sweta Dash, Katherine Nyswaner, Mungo J.B. Harvey, Ben King, Allison Woods, Neil O. Carragher, Asier Unciti, Enrique Poradosu, John Brognard
Journal: Journal of Clinical Oncology (2023)

e15133 Background: NXP900 (eCF506) is a novel potent and selective SRC family kinase (SFK) inhibitor, (IC 50 of 0.47 nM against YES1). NXP900 locks its target into its native “closed” conformation (type 1.5 inhibitor), thereby inhibiting both kinase activity and complex formation with protein partners (Temps et al. Cancer Res. 2021, 81, 5438-5450). In contrast, multi-kinase inhibitors, including dasatinib and bosutinib, block SRC in the active “open” conformation (type 1 inhibitors) promoting the association of SFK and signaling partners via allosteric facilitation of conformational protein activation (Higuchi et al. Cell Rep 2021, 34, 108876). YES1 gene amplification is prevalent in several squamous cancers including esophageal squamous cell carcinoma (ESCC), lung SCC, head and neck SCC, and bladder cancer, indicating that YES1 would be an attractive target in these cancer types. Moreover, crosstalk between YES1 and the Hippo pathway suggests that NXP900 may have a therapeutic potential in squamous cancers with Hippo pathway alterations. Methods: Animal strain: CD1 Nude mice (Charles River). Human ESCC cancer cell lines: KYSE70, OE21, KYSE410, KYSE30 and OE19 cells (Sigma), TE5, and TE14 (Riken). Xenograft tumors were generated by subcutaneous implantation on the right lower flank of the thigh at a cell density of 2x10 6 to 1x10 7 cells/mouse at 0.1 mL Matrigel/cell dilution volume per injection. Experiment groups: Vehicle, NXP900 (40 mg/kg); treatment: QD for 28 days, oral gavage. Colony formation assay: 500 cells of 4 cell lines (KYSE70, OE21, KYSE410 and KYSE30) and 1500 cells of 3 cell lines (OE19, TE5 and TE14) were seeded in 24 well plates in triplicates; and treated with NXP900 for 14 days followed by staining with crystal violet. Results: NXP900 strongly inhibited cell proliferation of KYSE70, KYSE410, KYSE30, OE21, OE19, TE5 and TE14 in a colony formation assay. NXP900 significantly inhibited the activating phosphorylation of SRC in KYSE70 cells at 10 nM, while no effect was observed on the inhibitory tyrosine residues on YES1/FYN at 250 nM. Oral administration of NXP900 in a KYSE70 xenograft mouse model with YES1 gene amplification, resulted in an average decrease of tumor volume of 71% while in the vehicle control group tumor volume increased by 472% (p ≤ 0.001), demonstrating significant tumor regression. On Day 27, a mean increase from baseline in body weight of 2.0% and 3.5% was seen in the NXP900 and control groups respectively, indicating good tolerability. Conclusions: NXP900 is a novel potent and selective YES1/SRC kinase inhibitor with subnanomolar IC 50 against YES1. NXP900 has marked antitumor efficacy in esophageal carcinoma models in vitro and in vivo providing substantial proof of concept for targeting solid tumors with YES1 and Hippo pathway alterations. IND enabling studies for NXP900 have been completed.
Safety and efficacy of transarterial chemoembolization combined with tyrosine kinase inhibitors and camrelizumab in the treatment of patients with advanced unresectable hepatocellular carcinoma.
Authors: Jinpeng Li, Yuntao Jia, Huihui Han, Yanyan Lin, Jinlong Song
Journal: Journal of Clinical Oncology (2023)

4079 Background: Combined systemic and local therapy is a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKI) and PD-1 antibodies are all recommended for patients with unresectable HCC (uHCC). This study was aimed to evaluate the efficacy and safety of TACE combined with TKIs and camrelizumab in the treatment of uHCC. Methods: In this multicenter, single-arm phase II trial (ChiCTR2000039508), patients with intermediate-stage uHCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a TKI agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight &lt;60 kg), sorafenib 400 mg bid or donafenib 200 mg bid until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) per modified RECIST. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR) and overall survival (OS). Results: From September 2020 to November 2021, 87 patients (81 men and 6 women; median age, 56 years) were enrolled. Among them, 43 (49.4%) patients had extrahepatic metastases, and 65 (74.7%) patients had HBV infection. As of September 28, 2022, the median duration of follow-up was 13.6 (0.83-24.9) months. A total of 34 patients (39.1%) died, and the median OS was not reached. The median PFS was 10.5 months (95% CI: 7.8-13.1). The ORR rate was 71.3% (62/87), and the DCR rate was 89.7% (78/87) per mRECIST. According to RECIST version 1.1, the ORR rate was 35.6% (31/87), and the DCR rate was 87.4% (76/87). The ORR and PFS showed consistent benefits in subgroups based on ECOG score, HBV infection, baseline alpha-fetoprotein level, combined TKI, and the number of TACE treatments. Ten patients (11.5%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response (pCR) and four achieved a major pathological response (MPR). The most common AEs were hypoproteinemia (92%), elevated lactate dehydrogenase (80.5%), elevated glutamic oxaloacetic transaminase (79.3%), elevated bilirubin (78.2%), abdominal pain (62.1%), nausea (33.3%), and RCCEP (26.4%). The incidence of grade 3-4 adverse reactions was 67.8%, and no treatment-related deaths occurred. Conclusions: TACE combined with TKI and camrelizumab showed promising clinical benefits. It can effectively control tumor progression and provide opportunities for resection with acceptable safety, which will bring great benefits to uHCC. Clinical trial information: ChiCTR2000039508 .